Cyproterone acetate

Cyproterone acetate
Clinical data
Trade names Androcur, Androcur Depot, Cyprostat, many others
AHFS/Drugs.com Micromedex Detailed Consumer Information
Pregnancy
category
  • X
Routes of
administration		 Oral, intramuscular injection
ATC code G03HA01 (WHO)
Legal status
Legal status
  • ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 100%[1]
Protein binding Albumin: 93%
Free: 7%[2][3][4][5]
Metabolism Hepatic (CYP3A4)[6][7]
Metabolites • 15β-OH-CPA (major)[1][8]
• Cyproterone (minor)[9]
• Acetic acid (minor)[9]
Biological half-life Oral: 38 hours[9][10]
Intramusclar: 72 hours[9][10]
Excretion Feces: 70%[9]
Urine: 30%[9]
Identifiers
Synonyms SH-80714; SH-714; NSC-81430;[11] 6-Chloro-1β,2β-dihydro-17α-hydroxy-3'H-cyclopropa(1,2)pregna-1,4,6-triene-3,20-dione acetate; 6-Chloro-17α-hydroxy-1α,2α-methylenepregna-4,6-diene-3,20-dione acetate; 6-Chloro-1,2α-methylene-17α-hydroxy-δ6-progesterone acetate
CAS Number 427-51-0 YesY
2098-66-0 (free alcohol)
PubChem (CID) 9880
IUPHAR/BPS 2865
DrugBank DB04839
ChemSpider 9496 YesY
UNII 4KM2BN5JHF YesY
KEGG D01368
ChEBI CHEBI:50743 YesY
ChEMBL CHEMBL139835 YesY
Chemical and physical data
Formula C24H29ClO4
Molar mass 416.94 g/mol
3D model (Jmol) Interactive image
  (verify)

Cyproterone acetate (abbreviated as CPA), sold alone under the brand name Androcur or with ethinyl estradiol (EE) as Diane or Diane-35 among others, is an antiandrogen and progestogen that is used in the treatment of androgen-related conditions like acne, hirsutism (excessive hair growth), early-onset puberty, and prostate cancer, as a component of hormone therapy for transgender women, and in oral contraceptives.[11][12][13] It is formulated and used both alone and in combination with an estrogen and is available for use both by mouth and by injection into muscle.

CPA blocks the effects of androgens like testosterone in the body, which it does by preventing them from interacting with their biological target, the androgen receptor (AR), and by reducing their production by the gonads and hence their concentrations in the body.[14] In addition, it has progesterone-like effects by activating the progesterone receptor (PR). CPA is well-absorbed, is extensively bound to plasma proteins, and has an elimination half-life of around 40 hours.[9][10]

Common side effects of non-contraceptive (i.e., high) dosages of CPA in men include gynecomastia (breast development) and feminization in general and in both men and women include hypogonadism (low sex hormone levels), reversible infertility, sexual dysfunction, mental symptoms like depression, fatigue, and irritability, vitamin B12 deficiency, and elevated liver enzymes. Rare but serious adverse reactions of CPA include blood clots, liver damage, and certain types of benign brain tumors (specifically prolactinomas and meningiomas). CPA can also cause adrenal insufficiency as a withdrawal effect if it is discontinued abruptly from a high dosage.

CPA was first marketed in 1973, and was the first antiandrogen to be introduced for medical use.[15] Other important antiandrogens besides CPA include spironolactone and bicalutamide.[16] The drug is available widely throughout the world,[17][18] but is notably not approved for use in the United States.[19]

Medical uses

Androgen-dependent conditions

CPA is used in the treatment of prostate cancer, precocious puberty, androgen-dependent skin and hair conditions such as acne, seborrhea, hirsutism (excessive hair growth), and androgenic alopecia (pattern hair loss), hyperandrogenism (e.g., in PCOS), and to reduce sex drive in sex offenders or men with paraphilias or hypersexuality.[20] CPA is also widely used as a component of hormone replacement therapy (HRT) for transgender women.[21] In the U.S., where CPA is not available, other drugs with antiandrogen properties like the diuretic spironolactone and the progestin medroxyprogesterone acetate are used instead to treat androgen-dependent conditions besides prostate cancer.[22]

In the treatment of acne in women, a formulation of low-dose CPA in combination with EE has been found to result in overall improvement in 75 to 90% of patients, with responses approaching 100% improvement.[23]

Hormonal contraception

The combination of CPA and EE, a formulation sometimes referred to as co-cyprindiol, has been available as a combined oral contraceptive since 1978.[24] This formulation is taken once daily for 21 days, followed by a 7-day free interval. CPA has also been available in combination with estradiol valerate (brand name Femilar) as a contraceptive in Finland since 1993.[25]

Contraindications

Use during pregnancy is contraindicated, and for women of childbearing age, CPA should be administered with a combined oral contraceptive.

Interactions

Inhibitors and inducers of the cytochrome P450 enzyme CYP3A4 may interact with CPA.

Side effects

Hypogonadism and feminization

Side effects in males resulting directly from the antiandrogen and antigonadotropic properties of CPA include physical demasculinization, gynecomastia (breast enlargement) and general physical feminization, breast pain/tenderness, galactorrhea (milk outflow), sexual dysfunction (including loss of libido and erectile dysfunction), impaired spermatogenesis, and reversible infertility.[15] In the treatment of men with prostate cancer, CPA has been described as causing "severe" suppression of libido and erectile potency, comparable to that seen with surgical castration.[26] Due to suppression of the production of estrogens, long-term use of high-dose CPA without concomitant estrogen therapy can result in the development of osteoporosis in both sexes.[27]

Depression

CPA has been associated with an increased rate of depression in both men and women.[28] It has been reported that as many as 20–30% of women treated with the drug for hirsutism (dosage range 25–100 mg) may show depressive symptoms.[29][30] Also, a study found that around 20% of women treated with Dianette (which contains only 2 mg CPA) for contraceptive purposes developed depression.[31] As the antiandrogen component of transgender HRT, treatment with CPA (as well as with spironolactone to a lesser extent) has also been associated with a significantly higher rate of depressive symptomatology in transgender women relative to treatment with GnRH analogues (which are more selective in their action and are considered not to have a significant risk of depression in this patient population (with concomitant supplementation of estrogen)).[32] The depressive effects of CPA may be related to its glucocorticoid, antiandrogen, and/or antigonadotropic effects, as glucocorticoids, antiandrogens (in men), and GnRH analogues have all been associated with depression.[33][34][35][36] Vitamin B12 deficiency induced by CPA might also or alternatively be a critical factor.[31] Because of the side effect of depression, CPA should be used with caution in individuals with a history of the condition, especially if severe.[37]

Vitamin B12 deficiency

High-dose CPA treatment has been found to produce vitamin B12 deficiency.[38][39] Low-dose (2 mg/day) CPA in combination with EE has also been associated with vitamin B12 deficiency.[40] It is notable that vitamin B12 deficiency is associated with depression, anxiety, irritability, and fatigue via depletion of central monoamine neurotransmitters,[41][42] and it has been suggested that this may be involved in the adverse neuropsychiatric consequences commonly observed with CPA therapy.[31] Serum vitamin B12 monitoring and supplementation as necessary is recommended during CPA treatment.[38][39][40]

Other side effects

CPA has been associated with the formation of stretch marks, due potentially to glucocorticoid activity and/or causing dry skin.[43]

Rare reactions

Blood clots

Used alone, CPA does not appear to have a significant effect on blood clotting factors, but in combination with EE, as in combined oral contraceptives, presents an increased risk of deep vein thrombosis.[44] Women who take contraceptive pills containing CPA have a 6- to 7-fold increased risk of developing thromboembolism compared to women not taking a contraceptive pill, and twice the risk of women who take a contraceptive pill containing levonorgestrel.[45] At least four cases of fatal venous thromboembolism have been attributed to low-dose CPA in combination with EE.[46]

Hepatotoxicity

The most serious potential side effect of CPA is hepatotoxicity.[47] A variety of manifestations of liver disease in association with CPA treatment have been documented, including immunoallergic cytotoxic reactions, cholestasis, autoimmune hepatitis, acute hepatitis, fulminant liver failure, and cirrhosis, as well as an increased risk of hepatocellular carcinoma.[48][49] Clinical features may include jaundice, fatigue, nausea, elevated liver enzymes, hepatic necrosis and inflammation, and features of hepatic decompensation.[49] Hepatotoxicity due to CPA therapy is most common in elderly patients who are treated with high dosages of the drug for prolonged periods of time, but has also occurred in younger patients.[48]

In a study of 1,685 patients treated with CPA, elevated liver enzymes were seen in 10% of patients at a dosage of 50 mg/day and in 20% of patients at a dosage of greater than 100 mg/day.[47] A study of 2,506 patients given 18–136 mg/day for less than 47.5 months per patient reported a rate of 9.6%.[48][49] In a trial of 89 prostate cancer patients who received high-dose CPA for 4 years, there were elevated liver enzymes in 28.2% of the patients.[49] Yet another study of 105 patients found a hepatotoxicity rate of 9.5%, with serious hepatic injury occurring in 3.8%.[49] In 2002, it was reported that there were 18 case reports of CPA-associated hepatitis in the medical literature, with 6 of the cases resulting in death.[47] In addition, a review article cited a report of 96 instances of hepatotoxicity that were attributed to CPA, and 33 of these instances resulted in death.[47] Moreover, a 2014 review found that 15 cases specifically of CPA-induced fulminant (sudden-onset and severe) liver failure had been reported to date, with only one of these cases not resulting in death.[49] As such, the prognosis of CPA-induced liver failure is fatal.[49]

The risk of hepatotoxicity and death associated with CPA treatment is the reason that CPA has not been approved by the FDA for use in the United States.[50] Patients being treated with high-dose CPA should be closely monitored with liver function tests.[51] The risk is dose-dependent, and the low doses of CPA used in birth control pills (2 mg) have been said to represent a non-significant risk.[52] However, a German woman who had been taking Diane-35 (containing 2 mg/day CPA) for contraception for 14 years died of liver cancer, and this led to a safety review by drug regulators and the eventual restriction of CPA throughout Europe for the indication of acne treatment in women.[46]

Hyperprolactinemia

High-dose CPA in combination with estrogen has been associated with a dramatically (400-fold) increased incidence of hyperprolactinemia in transgender women.[53] Estrogen alone has been associated only with single case reports of prolactinoma in this population.[53]

Meningiomas

Very rarely, high-dose (but not low-dose (i.e., contraceptive-dose)) CPA treatment has been associated with the incidence and aggravation of meningiomas (a type of usually-benign brain tumor).[54][55] For this reason, high-dose CPA is contraindicated in people with meningioma or a history of meningoma.[6][37]

Withdrawal

Adrenal insufficiency

Abrupt withdrawal of CPA can be harmful, and the package insert from Schering AG recommends that the daily dose be reduced by no more than 50 mg at intervals of several weeks. The concern is the manner in which CPA affects the adrenal glands. Due to its glucocorticoid activity, high levels of CPA may reduce ACTH, resulting in adrenal insufficiency if discontinued abruptly. In addition, although CPA reduces androgen production in the gonads, it can increase the production of adrenal androgens, in some cases resulting in an overall rise in testosterone levels.[56] Thus, the sudden withdrawal of CPA could result in undesirable androgenic effects. This is a particular concern because androgens, especially DHT, suppress adrenal function, further reducing corticosteroid production.[57]

Suppression of adrenal function and reduced response to adrenocorticotropic hormone (ACTH) have been reported with CPA treatment. As a result, adrenal insufficiency and hence low cortisol and aldosterone levels and ACTH responsiveness can occur upon discontinuation of CPA. Low aldosterone levels may lead to hyponatremia (sodium loss) and hyperkalemia (excess potassium). Patients taking CPA should have their cortisol levels and electrolytes monitored, and if hyperkalemia develops, should reduce the consumption of foods with high potassium content or discontinue the medication.

Pharmacology

CPA is known to possess the following pharmacological activity:

CPA does not have significant affinity for the estrogen receptor (ER) or for the mineralocorticoid receptor (MR).

CPA is said to be equipotent as a progestogen and antiandrogen.[65] CPA is said to be the most potent progestin of the 17α-hydroxyprogesterone group, reportedly being 1200-fold more potent than hydroxyprogesterone acetate, 12-fold more potent than medroxyprogesterone acetate, and 3-fold more potent than chlormadinone acetate.[65][66] CPA is also reportedly the most potent of the steroidal antiandrogens,[67] out of hundreds of other steroids.[24]

Antiandrogenic activity

CPA is a potent androgen receptor (AR) competitive antagonist.[58] It directly blocks endogenous androgens such as testosterone and dihydrotestosterone (DHT) from binding to and activating the AR, and thus prevents them from exerting their androgenic effects in the body. However, CPA, like spironolactone and other steroidal antiandrogens such as chlormadinone acetate and medroxyprogesterone acetate, is not actually a pure antagonist of the AR – that is, a silent antagonist – but rather is a very weak partial agonist.[58][68][69][70] Clinically, CPA generally behaves purely as an antiandrogen, as it displaces much more efficacious endogenous androgens such as T and DHT from interacting with the receptor and thus its net effect is usually to lower physiological androgenic activity. But unlike silent antagonists of the AR such as flutamide, CPA, by virtue of its slight intrinsic activity at the receptor, is inherently incapable of fully abolishing androgenic activity in the body and will always maintain at least some degree of it.

In accordance with its, albeit weak, capacity for activation of the AR, CPA has been found to stimulate androgen-sensitive carcinoma growth in the absence of other androgens, an effect which could be blocked by co-treatment with flutamide.[68][69] As a result, CPA may not be as effective in the treatment of certain androgen-sensitive conditions such as prostate cancer compared to non-steroidal antiandrogens with a silent antagonist profile at the AR such as flutamide, bicalutamide, and enzalutamide.[58][71] Indeed, CPA has never been found to extend life in prostate cancer patients when added to castration relative to castration alone, unlike non-steroidal antiandrogens.[16]

A paradoxical effect occurs with certain prostate cancer cells which have genetic mutations in their ARs. These altered ARs can be activated, rather than inhibited, by CPA. In such cases, withdrawal of CPA may result in a reduction in cancer growth, rather than the reverse.[72] This is known as antiandrogen withdrawal syndrome.

CPA may also have a slight direct inhibitory effect on 5α-reductase, though the evidence for this is sparse and conflicting.[73][74][75] In any case, the combination of CPA and finasteride, a well-established, selective 5α-reductase inhibitor, has been found to result in significantly improved effectiveness in the treatment of hirsutism relative to CPA alone, suggesting that if CPA does have any direct inhibitory effects on 5α-reductase, they must be far from maximal.[76][77]

Indirect estrogenic effects

Because CPA does not bind to the ER, and because it suppresses estrogen production via its action as an antigonadotropin, the drug produces no general estrogenic effects (direct or indirect) and is potently antiestrogenic at sufficient dosages. However, androgens strongly antagonize the action of estrogen in the breasts, so CPA can produce a sole indirect estrogenic effect of slight gynecomastia in males via its action as an antiandrogen. In any case, the incidence and severity of this side effect is less than that observed with non-steroidal antiandrogens such as flutamide and bicalutamide, which, in contrast, do not lower estrogen levels (and actually can increase them).[78][79]

Progestogenic activity

CPA is a highly potent progestogen.[80] The dosage needed to inhibit ovulation in women (i.e., to act as a contraceptive) is less than 1 mg per day,[81] and the drug is marketed as a contraceptive (combined with low-dose EE) at a dosage of 2 mg/day.[80][82]

Through its action as a progestogen, CPA has been found to significantly increase prolactin secretion and to induce extensive lobuloalveolar development of the mammary glands of female rhesus macaques.[83] In accordance, a study found that CPA, in all cases, induced full lobuloalveolar development of the breasts in transgender women treated with the drug in combination with estrogen for a prolonged period of time.[84][85][86] Pregnancy-like breast hyperplasia was observed in two of the subjects.[86] In contrast, the same study found that men with prostate cancer treated with a non-progestogenic antiandrogen like flutamide or bicalutamide and no estrogen produced only moderate and incomplete lobuloalveolar development of the breasts.[84] Based on the above research, it was concluded by the study authors that combined estrogenic and progestogenic action is required in transgender women for fully mature female-like histologic breast development (i.e., that includes complete lobuloalveolar maturation).[84][85] Also, it was observed that lobuloalveolar maturation reverses upon discontinuation of CPA after surgical castration, similarly to the case of mammary gland involution in postpartum women, indicating that continued progestogen treatment is necessary to maintain the histology.[84] It should be noted however that although these findings may have important implications in the context of lactation and breastfeeding, epithelial tissue accounts for approximately only 10% of breast volume (with the bulk of the breasts (80–90%) being represented by stromal or adipose tissue),[87][88][89][90] and it is uncertain to what extent, if any, that development of lobuloalveolar structures (a type of epithelial tissue) contributes to breast size and/or shape.[91]

The action of CPA as a progestogen is responsible for its antigonadotropic effects.[58][80]

Antigonadotropic effects

CPA has powerful antigonadotropic effects via activation of the PR.[26][58][58][80] In humans, it blunts the gonadotropin releasing hormone (GnRH)-induced secretion of gonadotropins,[92] and accordingly, markedly suppresses circulating levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) at high dosages. Consequently, progesterone (P4), androstenedione, T, DHT, and estradiol (E2) are also markedly lowered at high dosages, while an elevation in sex hormone-binding globulin (SHBG) and prolactin levels is observed.[93][94][95][96][97] CPA is able to lower circulating T concentrations by 70 to 80% in men at high dosages.[98] However, in spite of strong suppression of testosterone levels, CPA, at least by itself (e.g., without estrogen), is not able to reduce testosterone levels into the castrate range (<50 ng/dL), and testosterone levels may remain just above it at circulating levels of roughly 50 to 100 ng/dL.[99]

Although the reduction of sex steroid levels with CPA is predominantly mediated by its progestogenic and antigonadotropic activities, inhibition of steroidogenic enzymes by the drug may also contribute to this to some extent.[100]

Other actions

Glucocorticoid activity

Due to negative feedback on the hypothalamic-pituitary-adrenal (HPA) axis, administration of exogenous glucocorticoids such as prednisone and dexamethasone suppress the secretion of adrenocorticotropic hormone (ACTH) from the pituitary gland and the production of cortisol from the adrenal glands, resulting in adrenal suppression and atrophy and, upon discontinuation of the glucocorticoid, temporary adrenal insufficiency. Similarly, albeit relatively weakly, CPA has the ability to reduce ACTH and cortisol levels and produce adrenal gland shrinkage, as well as, upon discontinuation, adrenal insufficiency, in both animals and humans, indicating that it possesses weak glucocorticoid properties.[101][102][103][104][105][106][107] Paradoxically however, in vitro, CPA is an antagonist of the glucocorticoid receptor (GR)[60][108][109] and a suppressor of adrenal cortisol and corticosterone production by inhibiting the enzymes 3β-hydroxysteroid dehydrogenase and 21-hydroxylase,[103][110][111][112] which are antiglucocorticoid actions. This paradox may be explained by the fact that certain active metabolites of CPA, such as its major metabolite 15β-hydroxycyproterone acetate (which is present at serum levels approximately twice those of CPA in humans[8]),[113] are, contrarily, agonists of the GR,[114] and it can be assumed that their glucocorticoid actions overall significantly outweigh the simultaneous antiglucocorticoid actions of CPA. Both cyproterone and CPA, via their metabolites, have been found to possess glucocorticoid effects, and based on studies in mice, it has been suggested that CPA has approximately 1/5th the potency of prednisone as a glucocorticoid.[115]

While various studies have clearly shown reduced cortisol and ACTH levels and ACTH responsiveness in humans with CPA treatment, some studies contradict these findings and report no such effects even with high dosages.[114][116][117][118][119]

Megestrol acetate, medroxyprogesterone acetate, and chlormadinone acetate, steroidal progestins and close analogues of CPA, all similarly possess glucocorticoid properties and the potential for producing adrenal insufficiency upon their discontinuation.[120][121]

Binding to opioid receptors

CPA has been found to bind non-selectively to the opioid receptors, including the μ-, δ-, and κ-opioid receptor subtypes, albeit very weakly relative to its other actions (IC50 for inhibition of [3H]diprenorphine binding = 1.62 ± 0.33 µM).[122] It has been suggested that activation of opioid receptors could have the potential to explain the side effect of sedation sometimes seen at high doses with CPA treatment and/or its effectiveness in the treatment of cluster headaches.[122]

Pharmacokinetics

Absorption

The oral bioavailability of CPA is reported to be 100%.[1] However, it has also been said that CPA is poorly absorbed from the gastrointestinal tract and should be taken after the consumption of food, which it would be implied improves its absorption.[123]

Distribution

In terms of plasma protein binding, CPA does not bind to sex hormone-binding globulin or transcortin[124] and is instead bound exclusively to albumin (93%), with the remainder (7%) circulating free or unbound.[1][2][3][4][5]

Metabolism

CPA is metabolized primarily by hydroxylation via CYP3A4, forming the major active metabolite 15β-hydroxycyproterone acetate.[1][8] This metabolite circulates at concentrations approximately twice those of CPA, and has similar antiandrogen activity to that of CPA but only 10% of its activity as a progestogen.[1][8][125][126] As a result, the co-administration of CPA with drugs which inhibit CYP3A4 may increase its potency as a progestogen.[2]

A portion of ingested CPA is metabolized by hydrolysis into cyproterone and acetic acid.[127] However, unlike many other steroid esters, CPA is not extensively hydrolyzed, and much of the pharmacological activity of the drug is attributable to CPA itself in its unchanged form.[51] Cyproterone has approximately one-third the potency of CPA as an antiandrogen[128] in addition, cyproterone is completely devoid of progestogenic activity.[66]

The elimination half-life of oral CPA is relatively long at approximately 38 hours.[1][123] However, in spite of this, the drug is usually given in divided doses two to three times per day when it is used orally in the treatment of prostate cancer.[123] When given via depot intramuscular injection, circulating levels of CPA reach a peak at 82 hours and the drug has an elimination half-life of 72 hours.[9][10]

Excretion

CPA is excreted 70% in feces and 30% in urine.[9]

Chemistry

CPA is a pregnane steroid and an acetylated derivative of 17α-hydroxyprogesterone.[129] It is structurally related to other 17α-hydroxyprogesterone derivatives such as chlormadinone acetate, hydroxyprogesterone caproate, medroxyprogesterone acetate, and megestrol acetate.[129]

CPA is also known by the following chemical names:[130]

History

CPA was discovered in the early 1960s, and Rudolf Wiechert, a Schering employee, together with F. Neumann in Berlin filed for a patent as "progestational agent" in 1962.[131] Only one year after patent approval in 1965, Neumann published evidence of CPA's antiandrogenic effect in rats; he reported an "organizational effect of CPA on the brain".[132] During the same year, in 1966, prenatal administration of CPA in male rats was shown to cause urogenital malformations by a group in Lund, Sweden.[133] CPA started being used in animal experiments around the world to investigate how antiandrogens affected fetal sexual differentiation.

In 1970, the first human experiments with CPA began by measuring serum levels after oral administration,[134] rates of spermatogenesis, and hair growth in women. Starting in 1972, psychiatrists trialed "sexually deviant" persons with CPA.[135] In 1973, CPA was first approved in Europe, under the brand name Androcur.[136][137] Until the development of leuprolide, CPA was one of the few drugs used to treat precocious puberty. CPA was first marketed in combination with EE as an oral contraceptive in 1978 under the brand name Diane.[24]

Along with the steroidal benorterone (17α-methyl-B-nortestosterone; SKF-7690), cyproterone, BOMT (Ro 7-2340), and trimethyltrienolone (R-2956) and the non-steroidal flutamide and DIMP (Ro 7-8117), CPA was one of the first antiandrogens to be discovered and studied.[138][40][139][140]

Society and culture

Generic name

The English and generic name of CPA is cyproterone acetate and this is its USAN, BANM, and JAN.[17][11][18][141] The English and generic name of unesterified cyproterone is cyproterone and this is its INN and BAN,[11][141][142] while cyprotérone is the DCF and French name and ciproterone is the DCIT and Italian name.[17][18] The name of unesterified cyproterone in Latin is cyproteronum, in German is cyproteron, and in Spanish is ciproterona.[17][18] These names of cyproterone correspond for CPA to acétate de cyprotérone in French, acetato de ciproterona in Spanish, ciproterone acetato in Italian, cyproteronacetat in German, cyproteronacetaat in Dutch, and ciproteron acetat in Slavic.

CPA is also known by the developmental code names SH-80714, SH-714, and NSC-81430, while unesterified cyproterone is known by the code names SH-80881, SH-881, and NSC-758636.[11][18][141][17]

Brand names

CPA is marketed under brand names including Androcur, Androcur Depot, Androcur-100, Androstat, Asoteron, Cyprone, Cyproplex, Cyprostat, Cysaxal, Imvel, and Siterone.[17][18] When CPA is formulated in combination with EE, it is also known as co-cyprindiol, and brand names for this formulation include Andro-Diane, Bella HEXAL 35, Chloe, Cypretil, Cypretyl, Cyproderm, Diane, Diane Mite, Diane-35, Dianette, Dixi 35, Drina, Elleacnelle, Estelle, Estelle-35, Ginette, Linface, Minerva, Vreya, and Zyrona.[17][18] CPA is also marketed in combination with estradiol valerate as Climen, Climene, Elamax, and Femilar.[17]

Availability

CPA is widely available throughout the world[17][18] and is marketed in almost every country,[143] with the notable major exception of the United States.[19] The drug is marketed both alone and in combination with EE or estradiol valerate.[17][18] Specific places in which CPA is marketed include the United Kingdom, other European countries, Canada, Australia, New Zealand, South Africa, Central and South America, and East and Southeast Asia.[17][18]

Research

Aggression and self-injury

CPA has been investigated for use in reducing aggression and self-injurious behavior via its antiandrogen effects in conditions like autism spectrum disorders and dementia (e.g., Alzheimer's disease).[144]

Obsessive-compulsive disorder

CPA may be effective in the treatment of obsessive-compulsive disorder (OCD).[145] In very limited clinical research, it has been reported to be "considerably" effective in the treatment of OCD in women.[146][147]

Cluster headaches

CPA has been studied in the treatment of cluster headaches in men.[148]

References

  1. 1 2 3 4 5 6 7 Kuhl H (August 2005). "Pharmacology of estrogens and progestogens: influence of different routes of administration" (PDF). Climacteric. 8 Suppl 1 (sup1): 3–63. doi:10.1080/13697130500148875. PMID 16112947.
  2. 1 2 3 Bińkowska M, Woroń J (June 2015). "Progestogens in menopausal hormone therapy". Przegla̜d Menopauzalny = Menopause Review. 14 (2): 134–43. doi:10.5114/pm.2015.52154. PMID 26327902.
  3. 1 2 Schindler AE, Campagnoli C, Druckmann R, Huber J, Pasqualini JR, Schweppe KW, Thijssen JH (December 2003). "Classification and pharmacology of progestins" (PDF). Maturitas. 46 Suppl 1: S7–S16. doi:10.1016/j.maturitas.2003.09.014. PMID 14670641. Since there is no binding of CPA to SHBG and CBG in the serum, 93% of the compound is bound to serum albumin.
  4. 1 2 Wakelin SH, Maibach HI, Archer CB (1 June 2002). Systemic Drug Treatment in Dermatology: A Handbook. CRC Press. pp. 32–. ISBN 978-1-84076-013-2. It is almost exclusively bound to plasma albumin.
  5. 1 2 Hammond GL, Lähteenmäki PL, Lähteenmäki P, Luukkainen T (October 1982). "Distribution and percentages of non-protein bound contraceptive steroids in human serum". Journal of Steroid Biochemistry. 17 (4): 375–80. doi:10.1016/0022-4731(82)90629-X. PMID 6215538.
  6. 1 2 Dickman A (27 September 2012). Drugs in Palliative Care. OUP Oxford. pp. 137–138. ISBN 978-0-19-966039-1.
  7. ↑ Boarder M, Newby D, Navti P (25 March 2010). Pharmacology for Pharmacy and the Health Sciences: A Patient-centred Approach. OUP Oxford. pp. 632–. ISBN 978-0-19-955982-4.
  8. 1 2 3 4 Frith RG, Phillipou G (1985). "15-Hydroxycyproterone acetate and cyproterone acetate levels in plasma and urine". J. Chromatogr. 338 (1): 179–86. doi:10.1016/0378-4347(85)80082-7. PMID 3160716.
  9. 1 2 3 4 5 6 7 8 9 Georg F. Weber (22 July 2015). Molecular Therapies of Cancer. Springer. pp. 316–. ISBN 978-3-319-13278-5. The terminal half-life is about 38 h. A portion of the drug is metabolized by hydrolysis to cyproterone and acetic acid. However, in contrast to many other steroid esters hydrolysis is not extensive, and much of the pharmacological activity is exerted by the acetate form. Excretion is about 70% in the feces, mainly in the form of glucuronidated metabolites, and about 30% in the urine, predominantly as non-conjugated metabolites.
  10. 1 2 3 4 AAPL Newsletter (PDF). The Academy. 1998. CPA is 100% bioavailable when taken orally with a half life of 38 hours. The injectable form reaches maximum plasma levels in 82 hours and has a half life of about 72 hours.
  11. 1 2 3 4 5 J. Elks (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 339–. ISBN 978-1-4757-2085-3.
  12. ↑ Neumann F, Töpert M (November 1986). "Pharmacology of antiandrogens". Journal of Steroid Biochemistry. 25 (5B): 885–95. doi:10.1016/0022-4731(86)90320-1. PMID 2949114.
  13. ↑ IARC Working Group on the Evaluation of Carcinogenic Risks to Humans; World Health Organization; International Agency for Research on Cancer (2007). Combined Estrogen-progestogen Contraceptives and Combined Estrogen-progestogen Menopausal Therapy. World Health Organization. p. 437. ISBN 978-92-832-1291-1.
  14. ↑ Jonathan S. Berek (2007). Berek & Novak's Gynecology. Lippincott Williams & Wilkins. p. 1085. ISBN 978-0-7817-6805-4.
  15. 1 2 Sarah H. Wakelin (1 June 2002). Systemic Drug Treatment in Dermatology: A Handbook. CRC Press. p. 32. ISBN 978-1-84076-013-2.
  16. 1 2 Singh, Shankar; Gauthier, Sylvain; Labrie, Fernand (2000). "Androgen Receptor Antagonists (Antiandrogens) Structure-Activity Relationships". Current Medicinal Chemistry. 7 (2): 211–247. doi:10.2174/0929867003375371. ISSN 0929-8673. When compared to flutamide, [cyproterone acetate] has significant intrinsic androgenic and estrogenic activities. [...] The effects of flutamide and the steroidal derivatives, cyproterone acetate, chlormadinone acetate, megestrol acetate and medroxyprogesterone acetate were compared in vivo in female nude mice bearing androgen-sensitive Shionogi tumors. All steroidal compounds stimulated tumor growth while flutamide had no stimulatory effect [51]. Thus, CPA due to its intrinsic properties stimulates androgen-sensitive parameters and cancer growth. Cyproterone acetate added to castration has never been shown in any controlled study to prolong disease-free survival or overall survival in prostate cancer when compared with castration alone [152-155].
  17. 1 2 3 4 5 6 7 8 9 10 11 https://www.drugs.com/international/cyproterone.html
  18. 1 2 3 4 5 6 7 8 9 10 Index Nominum 2000: International Drug Directory. Taylor & Francis. January 2000. pp. 289–. ISBN 978-3-88763-075-1.
  19. 1 2 Loren S Schechter (22 September 2016). Surgical Management of the Transgender Patient. Elsevier Health Sciences. pp. 26–. ISBN 978-0-323-48408-4.
  20. ↑ Mario Maggi (17 November 2011). Hormonal Therapy for Male Sexual Dysfunction. John Wiley & Sons. p. 104. ISBN 978-1-119-96380-6.
  21. ↑ Jameson JL, de Kretser DM, Marshall JC, De Groot LJ (7 May 2013). Endocrinology Adult and Pediatric: Reproductive Endocrinology. Elsevier Health Sciences. ISBN 978-0-323-22152-8.
  22. ↑ Duker M, Malsch M (28 January 2013). Incapacitation: Trends and New Perspectives. Ashgate Publishing, Ltd. p. 77. ISBN 978-1-4094-7151-6.
  23. ↑ Bentham Science Publishers (September 1999). Current Pharmaceutical Design. Bentham Science Publishers. pp. 716–.
  24. 1 2 3 G. Plewig; A.M. Kligman (6 December 2012). ACNE and ROSACEA. Springer Science & Business Media. pp. 662,685. ISBN 978-3-642-59715-2.
  25. ↑ Fruzzetti F, Bitzer J (2010). "Review of clinical experience with estradiol in combined oral contraceptives". Contraception. 81 (1): 8–15. doi:10.1016/j.contraception.2009.08.010. PMID 20004267.
  26. 1 2 Iversen P, Melezinek I, Schmidt A (January 2001). "Nonsteroidal antiandrogens: a therapeutic option for patients with advanced prostate cancer who wish to retain sexual interest and function". BJU International. 87 (1): 47–56. doi:10.1046/j.1464-410x.2001.00988.x. PMID 11121992.
  27. ↑ Terrence Priestman (26 May 2012). Cancer Chemotherapy in Clinical Practice. Springer Science & Business Media. pp. 97–. ISBN 978-0-85729-727-3.
  28. ↑ Blume-Peytavi U, Whiting DA, Trüeb RM (26 June 2008). Hair Growth and Disorders. Springer Science & Business Media. pp. 181–. ISBN 978-3-540-46911-7.
  29. ↑ James Barrett (2007). Transsexual and Other Disorders of Gender Identity: A Practical Guide to Management. Radcliffe Publishing. p. 174. ISBN 978-1-85775-719-4.
  30. ↑ Barth JH, Cherry CA, Wojnarowska F, Dawber RP (July 1991). "Cyproterone acetate for severe hirsutism: results of a double-blind dose-ranging study". Clinical Endocrinology. 35 (1): 5–10. doi:10.1111/j.1365-2265.1991.tb03489.x. PMID 1832346.
  31. 1 2 3 Rushton DH (July 2002). "Nutritional factors and hair loss". Clinical and Experimental Dermatology. 27 (5): 396–404. doi:10.1046/j.1365-2230.2002.01076.x. PMID 12190640.
  32. ↑ Seal LJ, Franklin S, Richards C, Shishkareva A, Sinclaire C, Barrett J (December 2012). "Predictive markers for mammoplasty and a comparison of side effect profiles in transwomen taking various hormonal regimens". The Journal of Clinical Endocrinology and Metabolism. 97 (12): 442–8. doi:10.1210/jc.2012-2030. PMID 23055547.
  33. ↑ Boccardo F (August 2000). "Hormone therapy of prostate cancer: is there a role for antiandrogen monotherapy?". Critical Reviews in Oncology/Hematology. 35 (2): 121–32. doi:10.1016/S1040-8428(00)00051-2. PMID 10936469.
  34. ↑ Clive Peedell (2005). Concise Clinical Oncology. Elsevier Health Sciences. pp. 81–. ISBN 0-7506-8836-X.
  35. ↑ Damber JE (2005). "Endocrine therapy for prostate cancer". Acta Oncologica. 44 (6): 605–9. doi:10.1080/02841860510029743. PMID 16165920.
  36. ↑ Robert G. Lahita (9 June 2004). Systemic Lupus Erythematosus. Academic Press. pp. 797–. ISBN 978-0-08-047454-0.
  37. 1 2 Waken SH, Maibach HI, Archer CB (21 May 2015). Handbook of Systemic Drug Treatment in Dermatology (Second ed.). CRC Press. pp. 34–. ISBN 978-1-4822-2286-9.
  38. 1 2 Ralph M. Trüeb (26 February 2013). Female Alopecia: Guide to Successful Management. Springer Science & Business Media. pp. 46–. ISBN 978-3-642-35503-5.
  39. 1 2 Ramsay ID, Rushton DH (July 1990). "Reduced serum vitamin B12 levels during oral cyproterone-acetate and ethinyl-oestradiol therapy in women with diffuse androgen-dependent alopecia". Clinical and Experimental Dermatology. 15 (4): 277–81. doi:10.1111/j.1365-2230.1990.tb02089.x. PMID 2145099.
  40. 1 2 3 Bentham Science Publishers (September 1999). Current Pharmaceutical Design. Bentham Science Publishers. pp. 717,1110.
  41. ↑ Sadock BJ, Sadock VA (2010). Kaplan and Sadock's Pocket Handbook of Clinical Psychiatry. Lippincott Williams & Wilkins. pp. 582–. ISBN 978-1-60547-264-5.
  42. ↑ Musisi S, Jacobson S (14 April 2015). Brain Degeneration and Dementia in Sub-Saharan Africa. Springer. pp. 60–. ISBN 978-1-4939-2456-1.
  43. ↑ Mohan D, Taylor R, Mackeith JA (1998). "Cyproterone acetate and striae". International Journal of Psychiatry in Clinical Practice. 2 (2): 147–8. doi:10.3109/13651509809115348. PMID 24946296.
  44. ↑ Vasilakis-Scaramozza C, Jick H (October 2001). "Risk of venous thromboembolism with cyproterone or levonorgestrel contraceptives". Lancet. 358 (9291): 1427–9. doi:10.1016/S0140-6736(01)06522-9. PMID 11705493.
  45. ↑ Lidegaard Ø, Nielsen LH, Skovlund CW, Skjeldestad FE, Løkkegaard E (2011). "Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses: Danish cohort study, 2001-9". Bmj. 343: d6423. doi:10.1136/bmj.d6423. PMC 3202015Freely accessible. PMID 22027398.
  46. 1 2 Kromm J, Jeerakathil T (June 2014). "Cyproterone acetate-ethinyl estradiol use in a 23-year-old woman with stroke". Cmaj. 186 (9): 690–3. doi:10.1503/cmaj.130579. PMID 24491473.
  47. 1 2 3 4 Neil Kaplowitz (16 October 2002). Drug-Induced Liver Disease. CRC Press. pp. 618–. ISBN 978-0-203-90912-6.
  48. 1 2 3 Kim JH, Yoo BW, Yang WJ (May 2014). "Hepatic failure induced by cyproterone acetate: A case report and literature review". Canadian Urological Association Journal = Journal De l'Association Des Urologues Du Canada. 8 (5-6): E458–61. doi:10.5489/cuaj.1753. PMID 25024808.
  49. 1 2 3 4 5 6 7 Savidou I, Deutsch M, Soultati AS, Koudouras D, Kafiri G, Dourakis SP (December 2006). "Hepatotoxicity induced by cyproterone acetate: a report of three cases". World Journal of Gastroenterology. 12 (46): 7551–5. doi:10.3748/wjg.v12.i46.7551. PMID 17167851.
  50. ↑ Marius Duker (23 May 2016). Incapacitation: Trends and New Perspectives. Routledge. pp. 139–. ISBN 978-1-317-11767-4.
  51. 1 2 Berlex Canada, Inc. (2003-02-10). "Cyproterone Acetate Tablets and Injections Product Monographs (revised version)" (PDF).
  52. ↑ Adverse Drug Reactions Advisory Committee (February 2004). "Australian Adverse Drug Reactions Bulletin, Volume 23, Number 1".
  53. 1 2 Oettel M, Schillinger E (6 December 2012). Estrogens and Antiestrogens II: Pharmacology and Clinical Application of Estrogens and Antiestrogen. Springer Science & Business Media. pp. 544–. ISBN 978-3-642-60107-1.
  54. ↑ Meningeal Neoplasms—Advances in Research and Treatment: 2012 Edition: ScholarlyBrief. ScholarlyEditions. 26 December 2012. pp. 99–. ISBN 978-1-4816-0002-6.
  55. ↑ Jameson JL, De Groot LJ (25 February 2015). Endocrinology: Adult and Pediatric. Elsevier Health Sciences. pp. 6225–. ISBN 978-0-323-32195-2.
  56. ↑ van der Vange N, Blankenstein MA, Kloosterboer HJ, Haspels AA, Thijssen JH (April 1990). "Effects of seven low-dose combined oral contraceptives on sex hormone binding globulin, corticosteroid binding globulin, total and free testosterone". Contraception. 41 (4): 345–52. doi:10.1016/0010-7824(90)90034-S. PMID 2139843.
  57. ↑ Stalvey JR (July 2002). "Inhibition of 3beta-hydroxysteroid dehydrogenase-isomerase in mouse adrenal cells: a direct effect of testosterone". Steroids. 67 (8): 721–31. doi:10.1016/S0039-128X(02)00023-5. PMID 12117620.
  58. 1 2 3 4 5 6 7 8 Figg W, Chau CH, Small EJ (14 September 2010). Drug Management of Prostate Cancer. Springer. p. 71. ISBN 978-1-60327-829-4.
  59. ↑ Treatise on Water Science, Four-Volume Set. Newnes. 1 September 2010. pp. 1805–. ISBN 978-0-444-53199-5.
  60. 1 2 3 Honer C, Nam K, Fink C, Marshall P, Ksander G, Chatelain RE, Cornell W, Steele R, Schweitzer R, Schumacher C (May 2003). "Glucocorticoid receptor antagonism by cyproterone acetate and RU486". Molecular Pharmacology. 63 (5): 1012–20. doi:10.1124/mol.63.5.1012. PMID 12695529.
  61. ↑ Han C, Davis CB, Wang B (6 January 2010). Evaluation of Drug Candidates for Preclinical Development: Pharmacokinetics, Metabolism, Pharmaceutics, and Toxicology. John Wiley & Sons. pp. 92–. ISBN 978-0-470-57488-1.
  62. ↑ Lehmann JM, McKee DD, Watson MA, Willson TM, Moore JT, Kliewer SA (September 1998). "The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions". The Journal of Clinical Investigation. 102 (5): 1016–23. doi:10.1172/JCI3703. PMC 508967Freely accessible. PMID 9727070.
  63. ↑ Christians U, Schmitz V, Haschke M (December 2005). "Functional interactions between P-glycoprotein and CYP3A in drug metabolism". Expert Opinion on Drug Metabolism & Toxicology. 1 (4): 641–54. doi:10.1517/17425255.1.4.641. PMID 16863430.
  64. ↑ Ayub M, Levell MJ (July 1987). "Inhibition of rat testicular 17 alpha-hydroxylase and 17,20-lyase activities by anti-androgens (flutamide, hydroxyflutamide, RU23908, cyproterone acetate) in vitro". Journal of Steroid Biochemistry. 28 (1): 43–7. doi:10.1016/0022-4731(87)90122-1. PMID 2956461.
  65. 1 2 Runnebaum BC, Rabe T, Kiesel L (6 December 2012). Female Contraception: Update and Trends. Springer Science & Business Media. pp. 133–134. ISBN 978-3-642-73790-9.
  66. 1 2 3 Hughes A, Hasan SH, Oerter GW, Voss HE, Banner F, Neumann F, et al. (27 November 2013). Androgens II and Antiandrogens / Androgene II und Antiandrogene. Springer Science & Business Media. pp. 485, 489, 491. ISBN 978-3-642-80859-3.
  67. ↑ William B. Pratt (1994). The Anticancer Drugs. Oxford University Press. pp. 219–. ISBN 978-0-19-506739-2.
  68. 1 2 Luthy IA, Begin DJ, Labrie F (November 1988). "Androgenic activity of synthetic progestins and spironolactone in androgen-sensitive mouse mammary carcinoma (Shionogi) cells in culture". Journal of Steroid Biochemistry. 31 (5): 845–52. doi:10.1016/0022-4731(88)90295-6. PMID 2462135.
  69. 1 2 Térouanne B, Tahiri B, Georget V, Belon C, Poujol N, Avances C, Orio F, Balaguer P, Sultan C (February 2000). "A stable prostatic bioluminescent cell line to investigate androgen and antiandrogen effects". Molecular and Cellular Endocrinology. 160 (1-2): 39–49. doi:10.1016/s0303-7207(99)00251-8. PMID 10715537.
  70. ↑ Fritz MA, Speroff L (20 December 2010). Clinical Gynecologic Endocrinology and Infertility. Lippincott Williams & Wilkins. p. 80. ISBN 978-0-7817-7968-5. Retrieved 27 May 2012.
  71. ↑ Lewis J. Kampel (20 March 2012). Dx/Rx: Prostate Cancer: Prostate Cancer. Jones & Bartlett Publishers. p. 169. ISBN 978-1-4496-8695-6.
  72. ↑ Prostate Cancer Research Institute. "The Anti-Androgen Withdrawal Response". Retrieved 2005-08-31.
  73. ↑ Rabe T, Kowald A, Ortmann J, Rehberger-Schneider S (August 2000). "Inhibition of skin 5 alpha-reductase by oral contraceptive progestins in vitro". Gynecological Endocrinology. 14 (4): 223–30. doi:10.3109/09513590009167685. PMID 11075290.
  74. ↑ Stárka L, Sulcová J, Broulík P (1976). "Effect of cyproterone acetate on the action and metabolism of testosterone in the mouse kidney". Endokrinologie. 68 (2): 155–63. PMID 1009901.
  75. ↑ Raudrant D, Rabe T (2003). "Progestogens with antiandrogenic properties". Drugs. 63 (5): 463–92. doi:10.2165/00003495-200363050-00003. PMID 12600226.
  76. ↑ Tartagni M, Schonauer LM, De Salvia MA, Cicinelli E, De Pergola G, D'Addario V (April 2000). "Comparison of Diane 35 and Diane 35 plus finasteride in the treatment of hirsutism". Fertility and Sterility. 73 (4): 718–23. doi:10.1016/s0015-0282(99)00633-0. PMID 10731531.
  77. ↑ Sahin Y, Dilber S, Keleştimur F (March 2001). "Comparison of Diane 35 and Diane 35 plus finasteride in the treatment of hirsutism". Fertility and Sterility. 75 (3): 496–500. doi:10.1016/s0015-0282(00)01764-7. PMID 11239530.
  78. ↑ Neumann F, Kalmus J (1991). "Cyproterone acetate in the treatment of sexual disorders: pharmacological base and clinical experience". Experimental and Clinical Endocrinology. 98 (2): 71–80. doi:10.1055/s-0029-1211103. PMID 1838080.
  79. ↑ Schröder FH (1998). "Antiandrogens as monotherapy for prostate cancer". European Urology. 34 Suppl 3: 12–7. PMID 9854190.
  80. 1 2 3 4 Fritz MA, Speroff L (2011). Clinical Gynecologic Endocrinology and Infertility. Lippincott Williams & Wilkins. pp. 561–. ISBN 978-0-7817-7968-5.
  81. ↑ James VH, Pasqualini J (22 October 2013). Hormonal Steroids: Proceedings of the Sixth International Congress on Hormonal Steroids. Elsevier Science. pp. 400–. ISBN 978-1-4831-9067-9.
  82. ↑ Pharmacology of the Skin II: Methods, Absorption, Metabolism and Toxicity, Drugs and Diseases. Springer Science & Business Media. 6 December 2012. pp. 489–. ISBN 978-3-642-74054-1.
  83. ↑ Herbert DC, Schuppler J, Poggel A, Günzel P, El Etreby MF (1977). "Effect of cyproterone acetate on prolactin secretion in the female Rhesus monkey". Cell Tissue Res. 183 (1): 51–60. doi:10.1007/bf00219991. PMID 411573.
  84. 1 2 3 4 Kanhai RC, Hage JJ, van Diest PJ, Bloemena E, Mulder JW (January 2000). "Short-term and long-term histologic effects of castration and estrogen treatment on breast tissue of 14 male-to-female transsexuals in comparison with two chemically castrated men". The American Journal of Surgical Pathology. 24 (1): 74–80. doi:10.1097/00000478-200001000-00009. PMID 10632490.
  85. 1 2 Lawrence, Anne A. (2007). "Transgender Health Concerns": 473–505. doi:10.1007/978-0-387-31334-4_19.
  86. 1 2 Paul Peter Rosen (2009). Rosen's Breast Pathology. Lippincott Williams & Wilkins. pp. 31–. ISBN 978-0-7817-7137-5.
  87. ↑ Lorincz AM, Sukumar S (2006). "Molecular links between obesity and breast cancer". Endocrine-related Cancer. 13 (2): 279–92. doi:10.1677/erc.1.00729. PMID 16728564. Adipocytes make up the bulk of the human breast, with epithelial cells accounting for only approximately 10% of human breast volume.
  88. ↑ Howard BA, Gusterson BA (2000). "Human breast development". Journal of Mammary Gland Biology and Neoplasia. 5 (2): 119–37. PMID 11149569. In the stroma, there is an increase in the amount of fibrous and fatty tissue, with the adult nonlactating breast consisting of 80% or more of stroma.
  89. ↑ Sperling MA (10 April 2014). Pediatric Endocrinology. Elsevier Health Sciences. pp. 598–. ISBN 978-1-4557-5973-6. Estrogen stimulates the nipples to grow, mammary terminal duct branching to progress to the stage at which ductules are formed, and fatty stromal growth to increase until it constitutes about 85% of the mass of the breast. [...] Lobulation appears around menarche, when multiple blind saccular buds form by branching of the terminal ducts. These effects are due to the presence of progesterone. [...] Full alveolar development normally only occurs during pregnancy under the influence of additional progesterone and prolactin.
  90. ↑ Hagisawa S, Shimura N, Arisaka O (2012). "Effect of excess estrogen on breast and external genitalia development in growth hormone deficiency". Journal of Pediatric and Adolescent Gynecology. 25 (3): e61–3. doi:10.1016/j.jpag.2011.11.005. PMID 22206682. Estrogen stimulates growth of the nipples, progression of mammary duct branching to the stage at which ductiles are formed, and fatty stromal growth until it constitutes about 85% of the mass of the breast.
  91. ↑ Wierckx K, Gooren L, T'Sjoen G (May 2014). "Clinical review: Breast development in trans women receiving cross-sex hormones". The Journal of Sexual Medicine. 11 (5): 1240–7. doi:10.1111/jsm.12487. PMID 24618412.
  92. ↑ Donald RA, Espiner EA, Cowles RJ, Fazackerley JE (April 1976). "The effect of cyproterone acetate on the plasma gonadotrophin response to gonadotrophin releasing hormone". Acta Endocrinologica. 81 (4): 680–4. PMID 769466.
  93. ↑ Moltz L, Römmler A, Post K, Schwartz U, Hammerstein J (April 1980). "Medium dose cyproterone acetate (CPA): effects on hormone secretion and on spermatogenesis in men". Contraception. 21 (4): 393–413. doi:10.1016/s0010-7824(80)80017-5. PMID 6771095.
  94. ↑ Rost A, Schmidt-Gollwitzer M, Hantelmann W, Brosig W (1981). "Cyproterone acetate, testosterone, LH, FSH, and prolactin levels in plasma after intramuscular application of cyproterone acetate in patients with prostatic cancer". The Prostate. 2 (3): 315–22. doi:10.1002/pros.2990020310. PMID 6458025.
  95. ↑ Jeffcoate WJ, Matthews RW, Edwards CR, Field LH, Besser GM (August 1980). "The effect of cyproterone acetate on serum testosterone, LH, FSH, and prolactin in male sexual offenders". Clinical Endocrinology. 13 (2): 189–95. doi:10.1111/j.1365-2265.1980.tb01041.x. PMID 6777092.
  96. ↑ Grunwald K, Rabe T, Schlereth G, Runnebaum B (November 1994). "[Serum hormones before and during therapy with cyproterone acetate and spironolactone in patients with androgenization]". Geburtshilfe Und Frauenheilkunde (in German). 54 (11): 634–45. doi:10.1055/s-2007-1022355. PMID 8719011.
  97. ↑ Salva P, Morer F, Ordoñez J, Rodriguez J (1983). "Treatment of idiopathic hirsute women with two combinations of cyproterone acetate". International Journal of Clinical Pharmacology Research. 3 (2): 129–35. PMID 6237068.
  98. ↑ Wein AJ, Kavoussi LR, Novick AC, Partin AW, Peters CA (25 August 2011). Campbell-Walsh Urology: Expert Consult Premium Edition: Enhanced Online Features and Print, 4-Volume Set. Elsevier Health Sciences. pp. 2938–. ISBN 978-1-4160-6911-9.
  99. ↑ Wenderoth, U. K.; Jacobi, G. H. (1983). "Gonadotropin-releasing hormone analogues for palliation of carcinoma of the prostate". World Journal of Urology. 1 (1): 40–48. doi:10.1007/BF00326861. ISSN 0724-4983.
  100. ↑ Schürenkämper P, Lisse K (November 1982). "Effects of cyproterone on the steroid biosynthesis in the human ovary in vitro". Endokrinologie. 80 (3): 281–6. PMID 7166160.
  101. ↑ Ricardo Azziz (8 November 2007). Androgen Excess Disorders in Women. Springer Science & Business Media. pp. 382–. ISBN 978-1-59745-179-6.
  102. ↑ Girard J, Baumann JB, Bühler U, Zuppinger K, Haas HG, Staub JJ, et al. (1978). "Cyproteroneacetate and ACTH adrenal function". J. Clin. Endocrinol. Metab. 47 (3): 581–6. doi:10.1210/jcem-47-3-581. PMID 233676.
  103. 1 2 Panesar NS, Herries DG, Stitch SR (1979). "Effects of cyproterone and cyproterone acetate on the adrenal gland in the rat: studies in vivo and in vitro". J. Endocrinol. 80 (2): 229–38. doi:10.1677/joe.0.0800229. PMID 438696.
  104. ↑ El Etreby MF (1979). "Effect of cyproterone acetate, levonorgestrel and progesterone on adrenal glands and reproductive organs in the beagle bitch". Cell Tissue Res. 200 (2): 229–43. doi:10.1007/bf00236416. PMID 487397.
  105. ↑ Savage DC, Swift PG (1981). "Effect of cyproterone acetate on adrenocortical function in children with precocious puberty". Arch. Dis. Child. 56 (3): 218–22. doi:10.1136/adc.56.3.218. PMC 1627152Freely accessible. PMID 6260040.
  106. ↑ Stivel MS, Kauli R, Kaufman H, Laron Z (1982). "Adrenocortical function in children with precocious sexual development during treatment with cyproterone acetate". Clin. Endocrinol. (Oxf). 16 (2): 163–9. doi:10.1111/j.1365-2265.1982.tb03160.x. PMID 6279337.
  107. ↑ Hague WM, Munro DS, Sawers RS, Duncan SL, Honour JW (1982). "Long-term effects of cyproterone acetate on the pituitary adrenal axis in adult women". Br J Obstet Gynaecol. 89 (12): 981–4. doi:10.1111/j.1471-0528.1982.tb04650.x. PMID 6216913.
  108. ↑ Mercier L, Miller PA, Simons SS (1986). "Antiglucocorticoid steroids have increased agonist activity in those hepatoma cell lines that are more sensitive to glucocorticoids". J. Steroid Biochem. 25 (1): 11–20. doi:10.1016/0022-4731(86)90275-x. PMID 2875214.
  109. ↑ Poulin R, Baker D, Poirier D, Labrie F (1991). "Multiple actions of synthetic 'progestins' on the growth of ZR-75-1 human breast cancer cells: an in vitro model for the simultaneous assay of androgen, progestin, estrogen, and glucocorticoid agonistic and antagonistic activities of steroids". Breast Cancer Research and Treatment. 17 (3): 197–210. doi:10.1007/BF01806369. PMID 1645605.
  110. ↑ Pham-Huu-Trung MT, de Smitter N, Bogyo A, Girard F (1984). "Effects of cyproterone acetate on adrenal steroidogenesis in vitro". Horm. Res. 20 (2): 108–15. doi:10.1159/000179982. PMID 6237971.
  111. ↑ Lambert A, Mitchell RM, Robertson WR (1985). "On the site of action of the anti-adrenal steroidogenic effect of cyproterone acetate". Biochem. Pharmacol. 34 (12): 2091–5. doi:10.1016/0006-2952(85)90400-9. PMID 2988566.
  112. ↑ Heinze F, Teller WM, Fehm HL, Joos A (1978). "The effect of cyproterone acetate on adrenal cortical function in children with precocious puberty". Eur. J. Pediatr. 128 (2): 81–8. doi:10.1007/bf00496993. PMID 208851.
  113. ↑ Bhargava AS, Seeger A, Günzel P (1977). "Isolation and identification of 15-beta-hydroxy cyproterone acetate as a new metabolite of cyproterone acetate in dog, monkey and man". Steroids. 30 (3): 407–18. doi:10.1016/0039-128x(77)90031-9. PMID 413211.
  114. 1 2 Bhargava AS, Kapp JF, Poggel HA, Heinick J, Nieuweboer B, Günzel P (1981). "Effect of cyproterone acetate and its metabolites on the adrenal function in man, rhesus monkey and rat". Arzneimittelforschung. 31 (6): 1005–9. PMID 6266428.
  115. ↑ Broulik PD, Starka L (1975). "Corticosteroid-like effect of cyproterone and cyproterone acetate in mice". Experientia. 31 (11): 1364–5. doi:10.1007/bf01945829. PMID 1204803.
  116. ↑ van Wayjen RG, van den Ende A (1981). "Effect of cyproterone acetate on pituitary-adrenocortical function in man". Acta Endocrinol. 96 (1): 112–22. doi:10.1530/acta.0.0960112. PMID 6257015.
  117. ↑ Schürmeyer T, Graff J, Senge T, Nieschlag E (1986). "Effect of oestrogen or cyproterone acetate treatment on adrenocortical function in prostate carcinoma patients". Acta Endocrinol. 111 (3): 360–7. doi:10.1530/acta.0.1110360. PMID 2421511.
  118. ↑ van Wayjen RG, van den Ende A (1995). "Experience in the long-term treatment of patients with hirsutism and/or acne with cyproterone acetate-containing preparations: efficacy, metabolic and endocrine effects". Exp. Clin. Endocrinol. Diabetes. 103 (4): 241–51. doi:10.1055/s-0029-1211357. PMID 7584530.
  119. ↑ Holdaway IM, Croxson MS, Evans MC, France J, Sheehan A, Wilson T, et al. (1983). "Effect of cyproterone acetate on glucocorticoid secretion in patients treated for hirsutism". Acta Endocrinol. 104 (2): 222–6. doi:10.1530/acta.0.1040222. PMID 6227191.
  120. ↑ John A. Thomas (12 March 1997). Endocrine Toxicology, Second Edition. CRC Press. pp. 152–. ISBN 978-1-4398-1048-4.
  121. ↑ Nick Panay (31 August 2015). Managing the Menopause. Cambridge University Press. pp. 126–. ISBN 978-1-107-45182-7.
  122. 1 2 Gutiérrez M, Menéndez L, Ruiz-Gayo M, Hidalgo A, Baamonde A (June 1997). "Cyproterone acetate displaces opiate binding in mouse brain". European Journal of Pharmacology. 328 (1): 99–102. doi:10.1016/s0014-2999(97)83034-8. PMID 9203575.
  123. 1 2 3 Anderson J (2003). "The role of antiandrogen monotherapy in the treatment of prostate cancer". BJU Int. 91 (5): 455–61. PMID 12603397.
  124. ↑ Howard J.A. Carp, MB,BS, FRCOG (9 April 2015). Progestogens in Obstetrics and Gynecology. Springer. pp. 38–. ISBN 978-3-319-14385-9.
  125. ↑ Fischl FH. (2001). "Pharmacology of Estrogens and Gestagens" (PDF). In Krause & Pachemegg. Menopause andropause (PDF). Gablitz: Krause und Pachernegg. pp. 33–50. ISBN 3-901299-34-3.
  126. ↑ New Zealand Medicines; Medical Devices Safety Authority (2005-12-09). "Data Sheet: Diane 35 ED".
  127. ↑ Medicines and Healthcare products Regulatory Authority (2006-04-11). "Cyproterone Acetate" (PDF).
  128. ↑ Giorgi EP, Shirley IM, Grant JK, Stewart JC (March 1973). "Androgen dynamics in vitro in the human prostate gland. Effect of cyproterone and cyproterone acetate". The Biochemical Journal. 132 (3): 465–74. PMC 1177610Freely accessible. PMID 4125095.
  129. 1 2 John V. Knaus; John H. Isaacs (6 December 2012). Office Gynecology: Advanced Management Concepts. Springer Science & Business Media. pp. 150–. ISBN 978-1-4612-4340-3.
  130. ↑ https://chem.nlm.nih.gov/chemidplus/rn/427-51-0
  131. ↑ U.S. Patent 3,234,093
  132. ↑ Neumann F, Elger W (1966). "Permanent changes in gonadal function and sexual behaviour as a result of early feminization of male rats by treatment with an antiandrogenic steroid". Endokrinologie. 50: 209–225.
  133. ↑ Forsberg JG, Jacobsohn D, Norgren A (1968). "Modifications of reproductive organs in male rats influenced prenatally or pre- and postnatally by an "antiandrogenic" steroid (Cyproterone)". Zeitschrift Für Anatomie Und Entwicklungsgeschichte. Springer. 127 (2): 175–86. doi:10.1007/bf00521983. PMID 5692718.
  134. ↑ Tamm J, Voigt KD, Schönrock M, Ludwig E (January 1970). "The effect of orally administered cyproterone on the serum production in human subjects". Acta Endocrinologica. 63 (1): 50–8. PMID 5467021.
  135. ↑ Von Schumann HJ (1972). "Resocialization of sexually abnormal patients by a combination of anti-androgen administration and psychotherapy". Psychother Psychosom. 20 (6): 321–32.
  136. ↑ William Andrew Publishing (22 October 2013). Pharmaceutical Manufacturing Encyclopedia, 3rd Edition. Elsevier. pp. 1182–. ISBN 978-0-8155-1856-3.
  137. ↑ Tobias JS, Hochhauser D (3 October 2014). Cancer and its Management. Wiley. pp. 379–. ISBN 978-1-118-46871-5.
  138. ↑ T. Mann; C. Lutwak-Mann (6 December 2012). Male Reproductive Function and Semen: Themes and Trends in Physiology, Biochemistry and Investigative Andrology. Springer Science & Business Media. pp. 352–. ISBN 978-1-4471-1300-3.
  139. ↑ Anthony W. Norman; Gerald Litwack (28 June 2014). Hormones. Elsevier Science. pp. 508–. ISBN 978-1-4832-5810-2.
  140. ↑ W.I.P. Mainwaring (6 December 2012). The Mechanism of Action of Androgens. Springer Science & Business Media. pp. 53–. ISBN 978-3-642-88429-0.
  141. 1 2 3 I.K. Morton; Judith M. Hall (6 December 2012). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 89–. ISBN 978-94-011-4439-1.
  142. ↑ Christoph Zink (1 January 1988). Dictionary of Obstetrics and Gynecology. Walter de Gruyter. pp. 61–. ISBN 978-3-11-085727-6.
  143. ↑ F. William Danby (27 January 2015). Acne: Causes and Practical Management. John Wiley & Sons. pp. 142–. ISBN 978-1-118-23277-4.
  144. ↑ Geier DA, Kern JK, King PG, Sykes LK, Geier MR (2012). "An evaluation of the role and treatment of elevated male hormones in autism spectrum disorders". Acta Neurobiol Exp (Wars). 72 (1): 1–17. PMID 22508080.
  145. ↑ Judith L. Rapoport (1 January 1989). Obsessive-compulsive Disorder in Children and Adolescents. American Psychiatric Pub. pp. 229–231. ISBN 978-0-88048-282-0.
  146. ↑ Kellner M (2010). "Drug treatment of obsessive-compulsive disorder". Dialogues in Clinical Neuroscience. 12 (2): 187–97. PMC 3181958Freely accessible. PMID 20623923.
  147. ↑ López Ibor JJ, Cercós CL, Masiá CC (2004). Images of Spanish Psychiatry. Editorial Glosa, S.L. pp. 376–. ISBN 978-84-7429-200-8.
  148. ↑ Sicuteri F (1988). "Antiandrogenic medication of cluster headache". Int J Clin Pharmacol Res. 8 (1): 21–4. PMID 3366500.

Further reading

This article is issued from Wikipedia - version of the 12/2/2016. The text is available under the Creative Commons Attribution/Share Alike but additional terms may apply for the media files.